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Background: The problem of venous thromboembolic events (VTE) after incisional hernia repair remains relevant. According to the literature the frequency of VTE ranges from 0.2 to 4.2%. The data on risk factors of VTE in this cohort of patients are scarce. Aim of our study is to find frequency and risk factors for VTE development in patients who underwent surgery for incisional ventral hernia. Materials and methods: There were 240 patients enrolled in our retrospective study. We included patients, who were operated for incisional hernia in Saveljev University Surgery Clinic from January 2018 to December 2019. Compression duplex ultrasound of lower extremity veins was performed within median 3 days (min 1 day, max 7 days) after surgery for all participants. The primary endpoint was the occurrence of the VTE event, including deep venous thrombosis (DVT) and pulmonary embolism (PE). Results: VTE was detected in 19 patients, which accounted for 7.9% in analyzed cohort. All patients received standard pharmacological prophylaxis. There were 3 (1.3%) proximal, 16 (6.7%) distal DVT, in one patient (0.4%) distal thrombosis was complicated by symptomatic pulmonary embolism. In multivariate Cox proportional hazard model was found that component separation (HR 3.99, 95% CI 1.14–14.0, p = 0.03), duration of operation in hours (HR 1.67. 95% CI 1.13–2.5, p = 0.011) and body mass index (HR 1.13, 95% CI 1.02–1.2, p = 0.02) were statistically significant risk factors. Conclusion: The incidence of postoperative VTE in patients after incisional hernia repair is high with a predominant distal DVT as a thrombotic event. Component separation, duration of operation and body mass index are statistically significant factors of VTE in patients undergoing surgery for incisional hernia. [ABSTRACT FROM AUTHOR]

Several years ago a series of powerful millisecond radio bursts with close dispersion measures was detected toward the galaxy M31. Taking the hypothesis about the possible association of these radio bursts with a magnetar in M31 as a starting point, we have searched for periodic X-ray signal sources using data from the XMM-Newton X-ray telescope. As a result of our data analysis, we have identified a signal from the already known periodic X-ray source 3XMM J004301.4+413017, an accreting pulsar in a binary system. However, we have failed to detect new candidates. In particular, we have revealed no object that could be associated with the hypothetical magnetar responsible for the observed radio bursts that could have a luminosity erg s . [ABSTRACT FROM AUTHOR]

Regarding possible influence of medical therapy on VTE risk none of our patients received cyclooxygenase-2 inhibitors, systemic glucocorticoids, and hydroxychloroquine at the time of surgery. In our opinion, exclusion of some patients would have influenced the results by missing some data on incisional hernia patients' conditions. We appreciate the interest of Wang et al. [[1]] in our recent paper "Risk factors of venous thromboembolism after incisional ventral hernia repair" [[2]]. [Extracted from the article]

Purpose: To find out the prevalence and risk factors for abdominal wall hernias in the general Russian population.Methods: 783 residents of Kryukovo rural community (Central Russia) of 10 > years were enrolled. Medical history was taken and clinical examination was performed documenting hernia presence. Ultrasound examination was performed in inconclusive situations. We considered residents with hernias at the time of examination, as well as those who had previously undergone hernia repair, to be hernia positive.Results: There were 298 (38%) men and 485 (62%) women (mean age 49.3). Abdominal wall hernias have been found in 20.9% of population. 31.2% of men and 14.6% of women were affected (p < 0.0001). Umbilical hernias was found in 10.2%, groin hernias in 8.3%, incisional in 2.4% of residents. 72% of individuals with hernia reported local pain. 70% had never asked for medical advice before, 30% had undergone hernia repair before. Male gender, age, family history were confirmed as risk factors for any hernia with OR 3.9, 1.03 and 2.7, respectively (p < 0.01). For groin hernias male gender, age, family history and rough labour were confirmed with ORs 9.2, 1.03, 2.9 (p < 0.01) and 2.1 (p < 0.05). Risk factors for umbilical hernias were male gender with OR 2.2 (p < 0.01), age, family history and BMI with ORs 1.02, 1.8 and 1.08 (p < 0.05).Conclusions: This study is the first to demonstrate prevalence of abdominal wall hernias and its risk factors in Russia. The results confirm that hernias are common in a general population pointing the need for improvement of surgical activity. [ABSTRACT FROM AUTHOR]

The principal idea of the Virtual Observatory is to achieve real transparency for astronomical data, similar to transparency for all the world's documents in the World Wide Web. In the Virtual Observatory, all the world's astronomical data is available from one's desktop. All archives understand the same query language, can be accessed through a uniform interface, and diverse data can be analyzed with the same tools. In particular, facilities of the Virtual Observatory allow users to make a fast and correct analysis of objects from various surveys. It yields multi-photometry data on registered objects and makes it possible to determine stellar parameters. Methods of astronomical data analysis as well as their application to various areas of stellar astronomy are discussed in this paper. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Heredity plays an important role in the etiology of varicose veins (VVs). However, the genetic basis underlying this condition remains poorly understood. Our aim was to replicate top association signals from genome‐wide association studies (GWASs) for VVs of lower extremities using 2 independent datasets—our sample of ethnic Russian individuals (709 cases and 278 controls) and a large cohort of British residents from UK Biobank (10 861 cases and 397 594 controls). Associations of polymorphisms rs11121615, rs6712038, rs507666, rs966562, rs7111987, rs6062618, and rs6905288 were validated in the UK Biobank individuals at a Bonferroni‐corrected significance level. In Russian cohort, only rs11121615 reached a nominal significance level of P < .05. Results of original GWAS and replication studies were combined by a meta‐analysis, and polymorphisms listed above as well as rs111434909 and rs4463578 passed a genome‐wide significant threshold. Notably, the majority of these polymorphisms were located within or near genes involved in vascular development and remodeling, and regulation of inflammatory response. Our results confirm the role of these polymorphisms in genetic susceptibility to VVs and indicate the revealed genomic regions as good candidates for further fine‐mapping studies and functional analysis. Moreover, our findings implicate inflammation and abnormal vascular architecture in VVs pathogenesis. [ABSTRACT FROM AUTHOR]

Context. X-ray catalogues provide a wealth of information on many source types, ranging from compact objects to galaxies, clusters of galaxies, stars, and even planets. Thanks to the huge volume of X-ray sources provided in the 3XMM catalogue, along with many source specific products, many new examples from rare classes of sources can be identified. Aims. Through visualising spectra and lightcurves from about 80 observations included in the incremental part of the 3XMM catalogue, 3XMM-DR5, as part of the quality control of the catalogue, we identified two new X-ray sources, 3XMM J183333.1+225136 and 3XMM J184916.1+652943, that were highly variable. This work aims to investigate their nature. Methods. Through simple model fitting of the X-ray spectra and analysis of the X-ray lightcurves of 3XMM J183333.1+225136 and 3XMM J184916.1+652943, along with complementary photometry from the XMM-Newton Optical Monitor, Pan-STARRS and the Stella/WiFSIP and Large Binocular Telescope (LBT) spectra, we suggest that the two sources might be magnetic cataclysmic variables (CVs) of the polar type and we determine some of their properties. Results. Both CVs have very hard spectra, showing no soft excess. They are both situated in the local neighbourhood, located within ~1 kpc. 3XMM J183333.1+225136 has an orbital period of 2.15 h. It shows features in the lightcurve that may be a total eclipse of the white dwarf. 3XMM J184916.1+652943 has an orbital period of 1.6 h. Given that only a small sky area was searched to identify these CVs, future sensitive all sky surveys such as the eROSITA project should be very successful at uncovering large numbers of such sources. [ABSTRACT FROM AUTHOR]

We studied the effects of single nucleotide polymorphisms in the promoter regions of matrix metalloproteinase genes rs1799750 (-1607dupG) MMP1, rs243865 ( C-1306T) MMP2, rs3025058 ( -1171dupA) MMP3, and rs11568818 ( A-181G) MMP7 on the risk of varicose vein of the lower extremities in ethnical Russians, residents of the Russian Federation. We genotyped 536 patients with this pathology and 273 healthy participants without history of chronic venous disease. Association was examined using logistic regression analysis. None of the studied polymorphisms showed statistically significant association with the risk of varicose veins of the lower extremities. Our results provide evidence that these polymorphisms are not involved in the pathogenesis of varicose veins and cannot serve as markers of predisposition to this pathology. [ABSTRACT FROM AUTHOR]

The structure and properties of graphene, which is a two-dimensional layer of carbon atoms with a hexagonal crystal lattice, are considered. Graphene is a zero bandgap semiconductor with a nondissipative motion of Dirac electron-hole pairs, which provides a charge mobility of μ ∼ 10 cm V s. Methods of their production are considered. It is shown that graphenes are the most promising materials for application as nanoelectromechanical transducers and ultracapacitors. [ABSTRACT FROM AUTHOR]

We analyzed associations between single nucleotide polymorphisms (SNP) rs13155212 and rs7704267 in the AGGF1 gene (angiogenic factor with G patch and FHA domains 1) and the risk of risk of varicose veins of the legs in ethnic Russians. Frequencies of alleles, genotypes, and haplotypes were estimated in the sample of patients with this disease (474 patients) and in the control group of participants (478 volunteers) without a history of chronic venous disease. None of the studied polymorphisms was associated with the risk of this pathology. The whole AGGF1 gene sequence lies in a single block of high linkage disequilibrium, and both studied polymorphic variants are representative of all other SNP within this region. From these results, a conclusion was made that AGGF1 gene polymorphism does not affect the risk of varicose veins of the legs in ethnic Russians, or its contribution is low and can be revealed only after analysis of larger cohorts. [ABSTRACT FROM AUTHOR]

Automated search for star clusters in J, H, K s data from 2MASS catalog has been performed using the method developed by Koposov et al. (2008). We have found and verified 153 new clusters in the interval of the galactic latitude −24° < b < 24°. Color excesses E( B − V), distance moduli and ages were determined for 130 new and 14 yet-unstudied known clusters. In this paper, we publish a catalog of coordinates, diameters, and main parameters of all the clusters under study. A special web-site available at has been developed to facilitate dissemination and scientific usage of the results. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid α-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa−/−). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641±190% of normal (Gaa+/+) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa−/− control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.Gene Therapy (2005) 12, 1405–1409. doi:10.1038/sj.gt.3302550; published online 26 May 2005 [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins" in the previous issue.

Astrocyte to neuron reprogramming has been performed using viral delivery of neurogenic transcription factors in GFAP expressing cells. Recent reports of off-target expression in cortical neurons following adeno-associated virus (AAV) transduction to deliver the neurogenic factors have confounded our understanding of the efficacy of direct cellular reprogramming. To shed light on potential mechanisms that may underlie the neuronal off-target expression of GFAP promoter driven expression of neurogenic factors in neurons, two regionally distinct cortices were compared—the motor cortex (MC) and medial prefrontal cortex (mPFC)—and investigated: (1) the regional tropism and astrocyte transduction with an AAV5-GFAP vector, (2) the expression of Gfap in MC and mPFC neurons; and (3) material transfer between astrocytes and neurons. Using a Cre-based system (AAV5-hGFAP-Cre; Rosa26R-tdTomato reporter mice), regional differences were observed in tdTomato expression between the MC and mPFC. Interestingly, this correlated with the presence of a greater expression of Gfap mRNA in neurons in the mPFC. Additionally, intercellular material transfer of Cre and tdTomato was observed between astrocytes and neurons in both regions, albeit at very low frequencies. Our study highlights regionally distinct variation in neurons that warrants consideration when designing genetic constructs for gene therapies targeting astrocytes including astrocyte to neuron reprogramming. [ABSTRACT FROM AUTHOR]

Polyfunctional T cells programmed to perform activities such as degranulation of lytic enzymes and simultaneous production of multiple cytokines are associated with more effective control of viral infections. Immune responses to recombinant adeno-associated virus (rAAV) vector delivery systems can critically influence therapeutic efficacy and safety of gene therapy. However, knowledge of polyfunctional T cells in anti-AAV immune responses is scarce. To bridge this knowledge gap, we have investigated the polyfunctionality of primary human CD4 T cells from healthy donors after in-vitro exposure to rAAV2 or rAAV9 vectors. By performing proliferation assays of co-cultured T cells and rAAV pulsed monocyte-derived dendritic cells from healthy donors we demonstrate T cell reactivity of 43% and 50% to rAAV2 and rAAV9 vectors, respectively. We validated this frequency in a second screen using another set of healthy donors measuring CD25 and CD71 T cell activation. Single T cell secretome analysis of reactive donors uncovered a Th1 pro-inflammatory, cytolytic and chemoattractive cytokine release profile after stimulation with rAAV2 or rAAV9 vectors. 12.4% and 9.6% of the stimulated T cells displayed a polyfunctional cytokine response, respectively, including elevated polyfunctional inflammatory indices. These responses were characterized by cytokine clusters such as Granzyme B, MIP1-α and TNF-α released in combination by single T cells. Overall, our results provide insights into adaptive immunity with rAAV vector serotypes which will be important in advancing gene therapy safety, vector selection, immunogenicity assessment and better patient selection for AAV gene therapy. [ABSTRACT FROM AUTHOR]

This article presents an analysis of the results of a study on a promising method for producing functionally graded composite materials using "cold" gas dynamic spraying technology. In particular, for the Al–Al2O3 composite, the influence of the ceramic component content on the change in the coefficient of thermal linear expansion is determined. The results can be used in the design and creation of materials in thermally loaded components to reduce stresses by adjusting thermal gaps. [ABSTRACT FROM AUTHOR]

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Recently approved adeno-associated viral (AAV) vectors for liver monogenic diseases haemophilia A and B are exemplifying the success of liver-directed viral gene therapy. In parallel, additional gene therapy strategies are rapidly emerging to overcome some inherent AAV limitations, such as the non-persistence of the episomal transgene in the rapidly growing liver and immune response. Viral integrating vectors such as in vivo lentiviral gene therapy and non-viral vectors such as lipid nanoparticles encapsulating mRNA (LNP-mRNA) are rapidly being developed, currently at the preclinical and clinical stages, respectively. Macrophages are the first effector cells of the innate immune response triggered by gene therapy vectors. Macrophage uptake and activation following administration of viral gene therapy and LNP have been reported. In this study, we assessed the biodistribution of AAV, lentiviral, and LNP-mRNA gene therapy following the depletion of tissue macrophages by clodronate pre-treatment in neonatal and juvenile mice. Both neonatal and adult clodronate-treated mice showed a significant increase in lentiviral-transduced hepatocytes. In contrast, clodronate pre-treatment did not modify hepatocyte transduction mediated by hepatotropic AAV8 but reduced LNP-mRNA transfection in neonatal and juvenile animals. These results highlight the importance of age-specific responses in the liver and will have translational applications for gene therapy programs. [ABSTRACT FROM AUTHOR]

Gene therapy is a promising approach to the treatment of various inherited diseases, but its development is complicated by a number of limitations of the natural promoters used. The currently used strong ubiquitous natural promoters do not allow for the specificity of expression, while natural tissue-specific promoters have lowactivity. These limitations of natural promoters can be addressed by creating new synthetic promoters that achieve high levels of tissue-specific target gene expression. This review discusses recent advances in the development of synthetic promoters that provide a more precise regulation of gene expression. Approaches to the design of synthetic promoters are reviewed, including manual design and bioinformatic methods using machine learning. Examples of successful applications of synthetic promoters in the therapy of hereditary diseases and cancer are presented, as well as prospects for their clinical use. [ABSTRACT FROM AUTHOR]

Retinal diseases, leading to various visual impairments and blindness, are on the rise. However, the advancement of retinal gene therapies offers new hope for treatment of such diseases. Among different vector systems for conferring therapeutic genetic load to retinal cells, adeno-associated viruses (AAVs) have been most intensively explored and have already successfully gained multiple clinical approvals. AAV-based retinal gene therapies have shown great promise in treating retinal disorders, but usually rely on the heavily disruptive administration methods such as subretinal injection. This is because the clinically well-established, minimally invasive alternative of intravitreal injection (IVI) necessitates AAVs to traverse the retinal inner limiting membrane (ILM), which is hard to penetrate in higher eye models, like human or porcine eyes. Additionally, AAVs' natural transduction preference, known as tropism, is commonly not specific to cells of only one target retinal layer, which is another ongoing challenge in retinal gene therapy. This review examines strategies to overcome these obstacles with a focus on the potential of magnetic nanoparticles (MNPs) for improved retinal AAV delivery. [ABSTRACT FROM AUTHOR]

Background/Objectives: Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of intra-articular IL-1Ra injections in reducing OA-associated pain or cartilage degradation. Methods: Sustaining sufficient levels of IL-1Ra within the joints via adeno-associated virus (AAV)-mediated gene therapy presents a promising therapeutic strategy for OA. In this study, we constructed an IL-1Ra expression cassette employing intron insertion in the coding sequence (CDS) region to enhance protein expression levels. Furthermore, we incorporated precisely targeted liver-specific microRNA (miRNA) sequences to specifically downregulate transgene expression within hepatic tissues, thereby ensuring more targeted and controlled regulation of gene expression. Results: A rat model of OA was employed to compare the efficacy of AAV5 and AAV9 for IL-1Ra delivery at both high and low doses. It was observed that low-dose, but not high-dose, AAV9-IL-1Ra resulted in a significant reduction in joint swelling, accompanied by a decrease in the diameter of the affected area and the preservation of biomarkers associated with trabecular bone integrity. Conclusions: These results highlight the great potential of AAV9-IL-1Ra in osteoarthritis therapy, with the promise of achieving long-term improvement through a single intra-articular injection. [ABSTRACT FROM AUTHOR]

Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations. [ABSTRACT FROM AUTHOR]

Background: The risk factors and association of venous thromboembolism (VTE) following emergent ventral hernia repair (EVHR) remains uncertain. This aim of the study aims was to establish the predictors of VTE after EVHR and its influence on the long‐term outcomes. Methods: A total of 2093 patients from the MIMIC‐IV database who underwent EVHR were recruited. Multivariate logistic regression and nomogram models were developed to predict in‐hospital VTE and mortality. Calibration and receiver operating characteristic (ROC) curves were utilized to assess the model's effectiveness and reliability. Decision curve analysis (DCA) was performed to evaluate the net clinical benefits of the model. Results: The rate of in‐hospital VTE was 1.6% (33/2093) after EVHR. Four independent potential factors were established after multivariate analysis, and the abovementioned risk factors fit into the nomogram. The prediction model presented good performance metrics (C‐index: 0.857), the calibration and ROC curves demonstrated the accurate prediction power, and DCA indicated the superior net benefit of the established model. In‐hospital and 1‐year mortality rates were 0.8% (17/2093) and 4.1% (86/2076) after EVHR. The potential factors were included in the mortality prediction nomogram. The prediction model presented good performance metrics (C‐index of 0.957 and 0.828, respectively), the calibration and ROC curves were consistent with the actual results, and DCA indicated the superior net benefit of the established model. Conclusion: The nomogram, derived from the logistic regression model, demonstrated excellent predictive performance for VTE occurrence and prognosis in patients following EVHR. This model could serve as a valuable reference for clinical decision‐making regarding VTE prevention and for enhancing post‐EVHR prognosis. [ABSTRACT FROM AUTHOR]

A study is performed of the temperature dependences of the Hall coefficient, specific electrical resistance, and saturation magnetization for Fe60Co20Si8B12 and Fe58Co20Si12B10 alloys in amorphous and crystalline states. The relationship between these parameters is established and explained from the viewpoint of the theory of the anomalous Hall effect. Coefficients of the parameter of spin–orbital interaction are estimated on the basis of experimental data. [ABSTRACT FROM AUTHOR]

Rodents are commonly employed to model human liver conditions, although species differences can restrict their translational relevance. To overcome some of these limitations, researchers have long pursued human hepatocyte transplantation into rodents. More than 20 years ago, the first primary human hepatocyte transplantations into immunodeficient mice with liver injury were able to support hepatitis B and C virus infections, as these viruses cannot replicate in murine hepatocytes. Since then, hepatocyte chimeric mouse models have transitioned into mainstream preclinical research and are now employed in a diverse array of liver conditions beyond viral hepatitis, including malaria, drug metabolism, liver-targeting gene therapy, metabolic dysfunction-associated steatotic liver disease, lipoprotein and bile acid biology, and others. Concurrently, endeavors to cotransplant other cell types and humanize immune and other nonparenchymal compartments have seen growing success. Looking ahead, several challenges remain. These include enhancing immune functionality in mice doubly humanized with hepatocytes and immune systems, efficiently creating mice with genetically altered grafts and reliably humanizing chimeric mice with renewable cell sources such as patient-specific induced pluripotent stem cells. In conclusion, hepatocyte chimeric mice have evolved into vital preclinical models that address many limitations of traditional rodent models. Continued improvements may further expand their applications. [ABSTRACT FROM AUTHOR]

Over 80% of the world's deadliest pandemics are caused by viral infections, and vaccination remains the most effective way to prevent these infections from spreading. Since the discovery of the first vaccine over two centuries ago, several vaccine design technologies have been developed. Next-generation vaccines, based on mRNA and viral vector technologies, have recently emerged as alternatives to traditional vaccines. Adenoviral vector-based vaccines against coronavirus disease 2019 have demonstrated a more sustained antibody response as compared to mRNA vaccines. However, this has not been without complications, with a few cases of severe adverse events identified in vaccinated individuals, and the underlying mechanism is the subject of intense investigation. Adeno-associated viral vectors induce a weaker cellular immune response compared to adenoviral vectors, and it is mainly for this reason that there has been a diminished interest in exploring them as a vaccine platform until recently. This review will discuss recent developments and the potential of adeno-associated viral vectors as anti-viral vaccines. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated virus type 2 (rAAV) vectors have recently been used to achieve long-term, high level transduction in vivo. Further development of rAAV vectors for clinical use requires significant technological improvements in large-scale vector production. In order to facilitate the production of rAAV vectors, a recombinant herpes simplex virus type I vector (rHSV-1) which does not produce ICP27, has been engineered to express the AAV-2 rep and cap genes. The optimal dose of this vector, d27.1-rc, for AAV production has been determined and results in a yield of 380 expression units (EU) of AAV-GFP produced from 293 cells following transfection with AAV-GFP plasmid DNA. In addition, d27.1-rc was also efficient at producing rAAV from cell lines that have an integrated AAV-GFP provirus. Up to 480 EU/cell of AAV-GFP could be produced from the cell line GFP-92, a proviral, 293 derived cell line. Effective amplification of rAAV vectors introduced into 293 cells by infection was also demonstrated. Passage of rAAV with d27.1-rc results in up to 200-fold amplification of AAV-GFP with each passage after coinfection of the vectors. Efficient, large-scale production (>109 cells) of AAV-GFP from a proviral cell line was also achieved and these stocks were free of replication-competent AAV. The described rHSV-1 vector provides a novel, simple and flexible way to introduce the AAV-2 rep and cap genes and helper virus functions required to produce high-titer rAAV preparations from any rAAV proviral construct. The efficiency and potential for scalable delivery of d27.1-rc to producer cell cultures should facilitate the production of sufficient quantities of rAAV vectors for clinical application. [ABSTRACT FROM AUTHOR]

Conventional methods for rAAV purification that are based on cesium chloride ultracentrifugation have often produced vector preparations of variable quality and resulted in significant loss of particle infectivity. We report here several novel purification strategies that involve the use of non-ionic iodixanol gradients followed by ion exchange or heparin affinity chromatography by either conventional or HPLC columns. These methods result in more than 50% recovery of rAAV from a crude lysate and routinely produce vector that is more than 99% pure. More importantly, the new purification procedures consistently produce rAAV stocks with particle-to-infectivity ratios of less than 100, which is significantly better than conventional methods. The new protocol increases the overall yield of infectious rAAV by at least 10-fold and allows for the complete purification of rAAV in 1 working day. Several of these methods should also be useful for large-scale production. [ABSTRACT FROM AUTHOR]

Macroscopic fractal aggregates of cobalt are obtained by thermal evaporation of cobalt metal in an argon atmosphere and subsequent deposition on a silicon substrate heated to 1000 K. It is established that the fractal structure is formed by diffusion-limited aggregation of cobalt particles. The macroscopic fractal cobalt aggregates are ferromagnetic. © 1997 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The experimental results on the turbulent flow structure in a lattice matrix cell, which is a region between intersecting ribs on the opposite walls of a flat channel, are presented. The angle between the ribs was 2β = 60°, 90° and 120°; the Reynolds number calculated from the average velocity and hydraulic diameter of the channel was varied in the range Re = (1–7)·104. The aerodynamic characteristics of the flow inside a lattice matrix cell placed in a rectangular channel with a cross section of 20×150 mm and a length of 400 mm were measured using a two-component laser Doppler anemometer (LDA). The flow structure was studied in individual cells of 15×15 mm, formed by crossing ribs on the opposite channel walls. The complex three-dimensional structure of the flow in the matrix cells and strong turbulence of the flow in the near-wall regions are shown. The installation of ribs leads to a significant increase in hydraulic losses, especially at large crossing angles. [ABSTRACT FROM AUTHOR]

We have studied the effective density, electric conductivity, and thermo emf of compacted carbon nanotubes (NTs) and nanowhiskers (NWs). The effective densities of NTs and NWs are 1.6 and 2.8g/cm3 respectively. The thermo emf of compacted NWs (33μV/K) and NTs (7–8μV/K) make it possible to use these materials in sensors of molecular gases and biological objects. It is also recommended to introduce NWs and NTs as fillers into glue compositions possessing increased strength and electric conductivity, which are necessary for gluing metals. © 2005 Pleiades Publishing, Inc. [ABSTRACT FROM AUTHOR]

Engineered viral vectors designed to deliver genetic material to specific targets offer significant potential for disease treatment, safer vaccine development, and the creation of novel biochemical research tools. Viral tropism, the specificity of a virus for infecting a particular host, is often modified in recombinant viruses to achieve precise delivery, minimize off-target effects, enhance transduction efficiency, and improve safety. Key factors influencing tropism include surface protein interactions between the virus and host-cell, the availability of host-cell machinery for viral replication, and the host immune response. This review explores current strategies for modifying the tropism of recombinant viruses by altering their surface proteins. We provide an overview of recent advancements in targeting non-enveloped viruses (adenovirus and adeno-associated virus) and enveloped viruses (retro/lentivirus, Rabies, Vesicular Stomatitis Virus, and Herpesvirus) to specific cell types. Additionally, we discuss approaches, such as rational design, directed evolution, and in silico and machine learning-based methods, for generating novel AAV variants with the desired tropism and the use of chimeric envelope proteins for pseudotyping enveloped viruses. Finally, we highlight the applications of these advancements and discuss the challenges and future directions in engineering viral tropism. [ABSTRACT FROM AUTHOR]

Although supermassive black holes (SMBHs) reside in the heart of virtually every massive galaxy, it remains debated whether dwarf galaxies commonly host SMBHs. Because low-mass galaxies may retain memory of the assembly history of their black holes (BHs), probing the BH occupation fraction of local dwarf galaxies might offer insights into the growth and seeding mechanisms of the first BHs. In this work, we exploit the Western half of the eROSITA all-sky survey (covering 20,000 deg2) and compile a catalog of accreting SMBHs in local (D < 200 Mpc) dwarf galaxies. Cleaning our sample from X-ray background sources, X-ray binaries, and ultraluminous X-ray sources, we identify 74 active galactic nucleus (AGN)–dwarf galaxy pairs. Using this large and uniform sample, we derive the luminosity function of the dwarf galaxy AGN, fitting it with a power-law function and obtaining d N / d L X = (15.9 ± 2.2) × L X − 1.63 ± 0.05 . Measuring the offset between the dwarf galaxies' centroids and the X-ray sources, we find that ≈50% of the AGN are likely off-nuclear, in agreement with theoretical predictions. We compare the BH-to-stellar mass relation of our sample with the local and high-redshift relations, finding that our sources better adhere to the former, which suggests that local AGN across different mass scales undergo similar growth histories. Finally, we compare our sources with semianalytical models: while our sample's shallowness prevents distinguishing between different seeding models, we find that the data favor models that keep SMBHs in dwarf galaxies active at a moderate rate, motivating model improvement by comparison to AGN in the dwarf galaxy regime. [ABSTRACT FROM AUTHOR]

Adeno-associated viruses (AAV) are widely used as delivery vectors in clinical trials for in vivo gene therapy due to their unique features. Göttingen minipigs are a well-established animal model for several diseases and can be used for the efficacy and safety testing of AAV-based gene therapy. Pre-existing antibodies against AAV may influence the results of testing and, therefore, the animals should be tested for the presence of antibodies against relevant AAV serotypes. The detection of AAVs in pigs may be also important for the virus safety of xenotransplantation. In this study, we screened Göttingen minipigs from Ellegaard Göttingen Minipigs A/S, Denmark, and Marshall BioResources, USA, for antibodies against AAV1, AAV2, AAV6, AAV9 serotypes. Of the 20 animals tested, 18 had no neutralizing antibodies for all AAVs tested, none had antibodies against AAV9, only one had antibodies against AAV6, and the titers of antibodies against AAV1 and AAV2 were less than 1:100, with two exceptions. For total binding IgG, more individuals showed positivity for all the tested serotypes but, in general, the levels were low or zero. Three animals had no antibodies at all against the AAVs tested. Therefore, Göttingen minipigs could be considered an attractive animal model for gene therapy studies. Since some animals were negative for all AAVs tested, these may be selected and used as donor animals for xenotransplantation. [ABSTRACT FROM AUTHOR]

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T-cell responses against the transgene product upon AAV1 vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T-cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1 > MyD88 and TLR9 > MyD88 > type I IFN > IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. Further, even low-frequency CD8+ T-cell responses could eliminate transgene expression, even in MyD88- or IL-1R1-deficient animals that received a low vector dose. However, we provide evidence that CpG depletion of vector genomes and including TLR9 inhibitory sequences can synergize. When this construct was combined with the use of a muscle-specific promoter, transgene expression in muscle was sustained with minimal local or systemic CD8+ T-cell response. Thus, innate immune avoidance/blockade strategies by themselves, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of the redundancy of immune-activating pathways. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated viruses (rAAVs) have emerged as an attractive tool for gene delivery, and demonstrated tremendous promise in gene therapy and gene editing—therapeutic modalities with potential "one-and-done" treatment benefits compared to conventional drugs. Given their tropisms for the central nervous system (CNS) across various species including humans, rAAVs have been extensively investigated in both pre-clinical and clinical studies targeting neurodegenerative disease. However, major challenges remain in the application of rAAVs for CNS gene therapy, such as suboptimal vector design, low CNS transduction efficiency and specificity, and therapy-induced immunotoxicity. Therefore, continuing efforts are being made to optimize the rAAV vectors from their "core" genetic payloads to their "coat" or capsid structure. In this review, we describe current approaches for rAAV vector design tailored for transgene expression in the CNS, summarize the development of CNS-targeting AAV serotypes, and highlight recent advancements in AAV capsid engineering, aimed at generating a new generation of rAAVs with improved CNS tropism. Additionally, we discuss various administration routes for delivering rAAVs to the CNS and provide an overview of AAV-mediated gene therapies currently under investigation in clinical trials for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Oxidative stress is crucial in ulcerative colitis (UC) and colitis‐associated colorectal cancer (CAC). Intestinal epithelial cells (IECs) are an important component of the intestinal barrier. In previous studies, we have demonstrated that suppressing microRNA‐222‐3p (miR‐222‐3p) can protect against oxidative stress in IECs, which ameliorates colonic injuries in UC mice and prevents the conversion of UC to CAC. In this case, we hope to explore whether moxibustion can alleviate UC and CAC by inhibiting miR‐222‐3p based on mouse models of UC and CAC. After herb‐partitioned moxibustion (HPM) intervention, the disease activity index (DAI) and colon macroscopic damage index (CMDI) were significantly reduced in UC mice, and the number and volume of intestinal tumors were decreased considerably in CAC mice. Meanwhile, we found that HPM suppressed miR‐222‐3p expression and upregulated the mRNA and protein expression of Brahma‐related gene 1 (BRG1), nuclear factor erythroid 2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1), while inhibiting Kelch‐like ECH‐associated protein 1 (Keap1) expression in IECs of UC and CAC mice. With changes in reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH‐Px), and inflammatory cytokines interleukin (IL)‐1β and tumor necrosis factor (TNF)‐α), we verified that HPM protects against oxidative stress and inflammation in IECs of UC and CAC mice. The effect of HPM was inhibited in miR‐222‐3p overexpression mice, further demonstrating that the protective effect of HPM on UC and CAC mice was through inhibiting miR‐222‐3p. In summary, HPM regulates the BRG1/Nrf2/HO‐1 pathway by inhibiting miR‐222‐3p to attenuate oxidative stress in IECs in UC and CAC. [ABSTRACT FROM AUTHOR]

The concept of steady-state solutions to the Navier–Stokes equation is defined. Such solutions extend the notion of stationary ones, diminish exponentially over time, and have a fixed spatial field of velocities and constant pressure in the absence of external fields. A way of constructing these solutions is considered, and the problem of Taylor vortices is solved. A mathematical model of a tornado is proposed, within which a steady-state solution is obtained as an eigenfunction of the problem in the form of a vortex. A model for the formation of the structure of a gas cloud is proposed, based on the Navier–Stokes equation. It is shown that spiral arms arise from flows of gas moving outward, due to the Coriolis force. It is proved that the number of arms is even and their structure is independent of the angular velocity of rotation. We obtain a formula for the twist angle of the spirals, depending on the cloud parameters for when . [ABSTRACT FROM AUTHOR]

We analyzed images of every northern hemisphere Sd galaxy listed in the Third Reference Catalogue of Bright Galaxies with a relatively face-on inclination (θ ≤ 30°). Specifically, we measured the spiral arms' winding angle, ϕ, in 85 galaxies. We applied a novel black hole mass planar scaling relation involving the rotational velocities (from the literature) and pitch angles of each galaxy to predict central black hole masses. This yielded 23 galaxies, each having at least a 50% chance of hosting a central intermediate-mass black hole (IMBH), 102 < M • ≤ 105 M ☉. These 23 nearby (≲50 Mpc) targets may be suitable for an array of follow-up observations to check for active nuclei. Based on our full sample of 85 Sd galaxies, we estimate that the typical Sd galaxy (which tends to be bulgeless) harbors a black hole with log (M • / M ☉) = 6.00 ± 0.14 , but with a 27.7% chance of hosting an IMBH, making this morphological type of galaxy fertile ground for hunting elusive IMBHs. Thus, we find that a ∼106 M ☉ black hole corresponds roughly to the onset of bulge development and serves as a conspicuous waypoint along the galaxy–supermassive black hole coevolution journey. Our survey suggests that >1.22% of bright galaxies (B T ≲ 15.5 mag) in the local Universe host an IMBH (i.e., the "occupation fraction"), which implies a number density >4.96 × 10−6 Mpc−3 for central IMBHs. Finally, we observe that Sd galaxies exhibit an unexpected diversity of properties that resemble the general population of spiral galaxies, albeit with an enhanced signature of the eponymous prototypical traits (i.e., low masses, loosely wound spiral arms, and smaller rotational velocities). [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders, including traumatic injuries to the central nervous system (CNS) and neurodegenerative diseases, are characterized by early axonal damage, which does not regenerate in the adult mammalian CNS, leading to permanent neurological deficits. One of the primary causes of the loss of regenerative ability is thought to be a developmental decline in neurons' intrinsic capability for axon growth. Different molecules are involved in the developmental loss of the ability for axon regeneration, including many transcription factors. However, the function of microRNAs (miRNAs), which are also modulators of gene expression, in axon re-growth is still unclear. Among the various miRNAs recently identified with roles in the CNS, miR-17, which is highly expressed during early development, emerges as a promising target to promote axon regeneration. Here, we used adeno-associated viral (AAV) vectors to overexpress miR-17 (AAV.miR-17) in primary cortical neurons and evaluate its effects on neurite and axon regeneration in vitro. Although AAV.miR-17 had no significant effect on neurite outgrowth and arborization, it significantly enhances neurite regeneration after scratch lesion and axon regeneration after axotomy of neurons cultured in microfluidic chambers. Target prediction and functional annotation analyses suggest that miR-17 regulates gene expression associated with autophagy and cell metabolism. Our findings suggest that miR-17 promotes regenerative response and thus could mitigate neurodegenerative effects. [ABSTRACT FROM AUTHOR]

Anti-human immunodeficiency virus (HIV) broadly neutralizing antibodies (bNAbs) offer a promising approach for the treatment of HIV-1. The current paradigm for antibody therapy involves passive antibody transfer, requiring regular delivery of bNAbs in treating chronic diseases such as HIV-1. An alternative strategy is to use AAV-mediated gene transfer to enable in vivo production of desirable anti-HIV-1 antibodies. In this study, we investigated two sets of triple combinations of AAV9-vectors encoding different bNAbs: N6, 10E8, 10-1074 (CombiMab1), and VRC07-523, PGDM1400, 10-1074 (CombiMab2). We used CBAxC57Bl and C57BL/6 mouse models to characterize rAAV-induced antibody expression and to evaluate the neutralization capacity of mouse sera against a global panel of HIV-1 viral strains. rAAV9-mediated IgG expression varied between bNAb clones and mouse strains, with C57BL/6 mice exhibiting higher bNAb titers following rAAV delivery. Although CombiMab2 treatment elicited a higher IgG titer than CombiMab1, both combinations resulted in neutralization of all the viral strains from the global HIV-1 panel. Our data highlight the potential of AAV vectors as a long-term option for HIV-1 therapy. [ABSTRACT FROM AUTHOR]

Adeno-associated viruses (AAVs) have emerged as promising tools for gene therapy due to their safety and efficacy in delivering therapeutic genes or gene editing sequences to various tissues and organs. AAV serotype 9 (AAV9), among AAV serotypes, stands out for its ability to efficiently target multiple tissues, thus holding significant potential for clinical applications. However, existing methods for purifying AAVs are cumbersome, expensive, and often yield inconsistent results. In this study, we explore a novel purification strategy utilizing Dynabeads™ CaptureSelect™ magnetic beads. The AAV9 magnetic beads capture AAV9 with high specificity and recovery between 70 and 90%, whereas the AAVX magnetic beads did not bind to the AAV9. Through continuous interaction with AAVs in solution, these beads offer enhanced clearance of genomic DNA and plasmids even in the absence of endonuclease. The beads could be regenerated at least eight times, and the used beads could be stored for up to six months and reused without a significant reduction in recovery. The potency of the AAV9-purified vectors in vivo was comparable to that of iodixanol purified vectors. [ABSTRACT FROM AUTHOR]